Preparation of substituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity

ABSTRACT

Processes for preparing substituted 3-aryl-5-haloalkyl-pyrazoles and, specifically, for preparing C 1-5  alkyl esters of 5- 1-(C 1-5  alkyl)-4-halo-5-(C 1-3  haloalkyl)-1H-pyrazole-3-yl!-2,4-dihalo-benzoic acids such as isopropyl 5- 4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate, are presented. The described processes include novel approaches for forming phenyl-diketones, forming and alkylating pyrazoles, brominating heterocyclic compounds, oxidizing alkyl-substituted benzene compounds, and esterifying carboxylic acids. These processes may be combined to prepare 3-aryl-5-haloalkyl pyrazoles, or alternatively, used in subcombinations or individually to prepare intermediates or other useful compounds.

RELATED APPLICATION

This application is a continuation-in-part of application U.S. Ser. No.08/407,352, filed Mar. 20, 1995, which is a divisional of U.S. Ser. No.08/277,726 filed Jul. 20, 1994 now abandoned, now U.S. Pat. No.5,587,485.

BACKGROUND OF THE INVENTION

The present invention generally relates to the preparation ofsubstituted 3-aryl-5-haloalkyl-pyrazoles having herbicidal activity, andspecifically, to novel processes for preparing C₁₋₅ alkyl esters of 5-1-(C₁₋₅ alkyl)-4-halo-5-(C₁₋₃haloalkyl)-1H-pyrazole-3-yl!-2,4-dihalo-benzoic acids such as isopropyl5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate.While the invention is preferably directed to the preparation of such3-aryl-5-haloalkyl-pyrazoles, the invention also relates to theindividual process steps for forming phenyl-diketones, forming andalkylating pyrazoles, brominating pyrazoles and other heterocycliccompounds, oxidizing alkyl-substituted benzene compounds, andesterifying carboxylic acids.

Various substituted aryl-pyrazole compounds are known and used aschemical intermediates, pharmaceuticals and herbicides. Exemplary U.S.Patents include U.S. Pat. No. 3,326,662 to Tomoyoshi et al., U.S. Pat.No. 3,948,937 to Johnson et al., U.S. Pat. No. 4,008,249 to Fischer,deceased et al., U.S. Pat. No. 4,072,498 to Moon et al., U.S. Pat. No.4,260,775 to Plath et al., U.S. Pat. No. 4,468,871 to Ebel et al., U.S.Pat. No. 4,752,326 to Ohyama et al., U.S. Pat. No. 5,032,165 to Miura etal., U.S. Pat. No. 5,045,106 to Moedritzer et al. A variety of3-aryl-5-haloalkyl pyrazoles are disclosed in U.S. Pat. Nos. 5,281,571and 5,489,571 to Woodard et al.

Processes are generally known for making aryl-pyrazole compounds. U.S.Pat. No. 5,281,571 to Woodard et al. sets forth a method for preparingsubstituted 3-aryl-5-haloalkyl-pyrazoles. Briefly, an acetophenonehaving a methyl substituent on the phenyl moiety is reacted with anester in the presence of a base to form a phenyl diketone, which issubsequently isolated and then cyclized by treatment with hydrazine. Theresulting aryl-pyrazole is subjected to further process steps, includingN-alkylation and halogenation of the pyrazole moiety, oxidation of themethyl group on the phenyl moiety to form a benzoic acid, and formationof benzoic acid derivatives thereof.

While methods such as these are suitable for preparing substituted3-aryl-5-haloalkyl-pyrazoles, the methods are not optimized with regardto minimizing the expense of reagents, maximizing the selectivity ofregioisomers, or maximizing product yields and throughput.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to optimize theprocess steps for preparing 3-aryl-5-haloalkyl pyrazoles with respect tocost, reliability, selectivity, yield and throughput. It is also anobject of the invention to provide improved protocols for bromination ofheterocyclic compounds, for oxidation of alkyl-substituted benzenesubstrates and for esterification of substituted or unsubstitutedcarboxylic acids.

Briefly, therefore, the present invention is directed to a process forpreparing a compound of Formula IIIb ##STR1## An acetophenone of FormulaIIIa ##STR2## is acylated with a haloacylhalide of Formula A1 ##STR3##which has a fully halogenated α-carbon. In this process: Ar is phenyl orsubstituted phenyl, R² is C₁₋₃ haloalkyl, and Z is halogen.

The invention is also directed to a process for preparing a compound ofFormula IIId ##STR4## A phenyl-diketone of Formula IIIb ##STR5## iscondensed with hydrazine in a reaction mixture to form analkyl-pyrazole-precursor intermediate. The hydrazine is present in thereaction mixture in a stoichiometric excess amount relative to thephenyl-diketone. The amount of excess hydrazine is at least about 15mole percent of the sum of the molar amount of unreacted phenyl-diketoneand the molar amount of intermediate formed. Excess hydrazine is thenremoved from the reaction mixture, and the intermediate is alkylatedwith an alkylating agent. In this process: Ar is phenyl or substitutedphenyl; R¹ is alkyl or alkyl substituted with halogen, amino, nitro,cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio; andR² is alkyl, hydroxy, alkoxy, acyl, carboxylic acid and aldehyde, amideand ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl.

In another process for preparing a compound of Formula IIId, aphenyl-diketone of Formula IIIb is condensed with hydrazine in areaction mixture to form an alkyl-pyrazole-precursor intermediate.Hydrazine is present in the reaction mixture in a stoichiometric excessamount relative to the phenyl-diketone. The reaction mixture has anorganic phase and an aqueous phase, and hydrazine is removed from thereaction mixture by removing the aqueous phase from the reactionmixture. The intermediate is then alkylated with an alkylating agent.Ar, R¹ and R² are defined in this process as in the process immediatelypreceding.

The invention is directed as well to a process for preparing analkylated pyrazole compound of Formula IIIe ##STR6## comprisingcondensing a phenyl-diketone of Formula IIIb with hydrazine in areaction mixture to form an alkyl-pyrazole-precursor intermediate. Theintermediate is alkylated under acidic conditions with an alkylatingagent. Ar, and R¹ are defined as in the process immediately preceding.R² is alkyl, hydroxy, alkoxy, acyl, carboxylic acid and aldehyde, amideand ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl. R² is preferably an electron withdrawing group andmost preferably a haloalkyl.

The invention is additionally directed to a process for regioselectivelyalkylating a 3(5)-aryl-5(3)-haloalkyl-pyrazole. A compound of FormulaIIIc, ##STR7## is alkylated with an alkylating agent withoutdeprotonating the N-hydrogen of the compound of Formula IIIc. Theresulting 3-aryl isomer of a 1-alkyl-3(5)-aryl-5(3)-haloalkyl-pyrazolehas the Formula IIIe ##STR8## While the reaction also results in theformation of a corresponding 5-aryl isomer thereof, the amount of 3-arylisomer formed is at least about 90% of the total amount of1-alkyl-3(5)-aryl-5(3)-haloalkyl-pyrazole formed. In this process: Ar isphenyl or substituted phenyl; R¹ is C₁₋₅ alkyl; and R² is C₁₋₃haloalkyl.

The invention is directed, moreover, to a process for brominating aheterocyclic substrate. The heterocyclic substrate is reacted with abromide salt under oxidizing conditions.

The invention is further directed to a process for directly oxidizing analkyl-substituted benzene substrate. The substrate is reacted withmolecular oxygen in the presence of metal salt catalyst and benzoylperoxide.

The invention is directed to processes for esterifying a carboxylic acidsubstrate. In a first esterification protocol, the carboxylic acid isreacted with a halogenating agent, and the resulting acid halide isesterified to form the corresponding carboxylic acid ester. Theesterification reagent used in this process is formed by mixing analcohol and an acylhalide. In a second, and independent esterificationprotocol, a carboxylic acid substrate is esterified with atrialkylorthoester of Formula F1 ##STR9## to form a carboxylic acidester. In this process, R¹⁰ is C₃₋₅ alkyl and R¹¹ is hydrogen or alkyl.

The present invention is also directed to processes for preparing acompound of Formula I ##STR10## A compound of Formula If ##STR11## ishalogenated to form an acid halide and the acid halide is thenesterified with an esterification reagent. The esterification reagent isformed by mixing an alcohol of Formula R¹⁰ OH and an acylhalide. In thisprocess: R¹ is C₁₋₅ alkyl; R² is C₁₋₃ haloalkyl; R³, R⁵ and R⁶ arehalogen; and R¹⁰ is C₃₋₅ alkyl.

In another process for preparing a compound of Formula I, a compound ofFormula If ##STR12## is esterified with a trialkylorthoester of FormulaF1 ##STR13## R¹, R², R³, R⁵, R⁶ and R¹⁰ are defined as in theimmediately preceding process and R¹¹ is hydrogen or alkyl.

In an additional process for preparing a compound of Formula I, acompound of Formula Ie ##STR14## is brominated with a bromide salt underoxidizing conditions to form a compound of Formula If and the compoundof Formula If is esterified. In this process: R¹, R², R⁵, R⁶ and R¹⁰ aredefined as in the immediately preceding process and R³ is bromo.

In a further process for preparing a compound of Formula I, a compoundof Formula Id ##STR15## is oxidized with molecular oxygen in thepresence of metal salt catalyst, catalyst promoter and benzoyl peroxideto form a compound of Formula Ie ##STR16## The compound of Formula Ie isthen halogenated to form a compound of Formula If, which is itselfsubsequently esterified. R¹, R² R⁵, R⁶ and R¹⁰ are as defined in theimmediately preceding process. R³ is halogen.

In still another process for preparing compounds of Formula I, acompound of Formula Ib ##STR17## is condensed with hydrazine in areaction mixture to form an alkyl-pyrazole-precursor intermediate. Theintermediate is then alkylated with an alkylating agent under acidicconditions to form a compound of Formula Id, ##STR18## The compound ofFormula Id is then oxidized to form a compound of Formula Ie, which issubsequently halogenated to form a compound of Formula If, which issubsequently esterified. In this process, R¹, R², R³, R⁵, R⁶ and R¹⁰ aredefined as in the immediately preceding process.

In an additional process for forming a compound of Formula I, a compoundof Formula Ia ##STR19## is acylated with a haloacylhalide having a fullyhalogenated α-carbon and represented structurally as Formula A1##STR20## The resulting compound of Formula Ib is condensed withhydrazine to form an alkyl-pyrazole-precursor intermediate. Theintermediate is alkylated with an alkylating agent to form a compound ofFormula Id, which is oxidized to form a compound of Formula Ie, which ishalogenated to form a compound of Formula If, which is esterified toform a compound of Formula I. In this process, R¹, R², R³, R⁵, R⁶ andR¹⁰ are defined as in the process immediately preceding.

In still a further process for preparing a compound of Formula I, acompound of Formula Ia is acylated with a haloacetylhalide or an alkylhaloacetate to form a phenyl diketone of Formula Ib. The phenyl-diketoneis condensed with hydrazine in a reaction mixture to form analkyl-pyrazole-precursor intermediate. The reaction mixture has anorganic phase and an aqueous phase, and hydrazine is present in thereaction mixture in a stoichiometric excess amount relative to thecompound of Formula Ib. The reaction mixture is heated to dissolve intothe organic phase any amount of precipitate which may have formed and toseparate the aqueous phase from the organic phase. Excess hydrazine isthen removed from the reaction mixture by removing the aqueous phasefrom the reaction mixture. The intermediate is alkylated with analkylating agent under acidic conditions to form a compound of FormulaId, which is subsequently oxidized with molecular oxygen in the presenceof metal salt catalyst, halide salt and acetone promoter and benzoylperoxide to form a compound of Formula Ie, which is then halogenated toform a compound of Formula If, which is then esterified to form acompound of Formula I. In this process, R¹, R², R³, R⁵, R⁶ and R¹⁰ areas defined for the immediately preceding process.

The present invention is further directed to a process for preparing acompound of Formula II ##STR21## In this process, a compound of FormulaIIa ##STR22## is acylated with trifluoroacetylhalide or ethyltrifluoroacetate to form a compound of Formula IIb, ##STR23## Thecompound of Formula IIb is then condensed with hydrazine in a reactionmixture to form an alkyl-pyrazole-precursor intermediate. Hydrazine ispresent in the reaction mixture in a stoichiometric excess amountrelative to the compound of Formula Ib. The reaction mixture, which hasan organic phase and an aqueous phase, is then heated to dissolve intothe organic phase any amount of precipitate which may have formed. Suchheating also facilitates separation of the aqueous phase from theorganic phase layers. Excess hydrazine is removed from the reactionmixture by removing the aqueous phase. The intermediate is thenalkylated with a methylating agent under acidic conditions to form acompound of Formula IId, ##STR24## The compound of Formula IId isoxidized with molecular oxygen in the presence of metal salt catalyst,halide salt, acetone and benzoyl peroxide to form a compound of FormulaIIe, ##STR25## The compound of Formula IIe is brominated with a bromidesalt under oxidizing conditions to form a compound of Formula IIf##STR26## which is then esterified to form a compound of Formula II.

Other features and objects of the present invention will be in partapparent to those skilled in the art and in part pointed outhereinafter.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes novel process steps for formingphenyl-diketones, forming and alkylating pyrazoles, brominatingpyrazoles and other heterocyclic compounds, oxidizing alkyl-substitutedbenzene compounds, and esterifying carboxylic acids. These steps may becombined to prepare 3-aryl-5-haloalkyl pyrazoles, or alternatively, usedin subcombinations or individually to prepare intermediates or othercompounds. The bromination, oxidation and esterification processespresented herein are particularly suited to a broader range ofsubstrates, as detailed below. The methods presented herein confersignificant advantages over the prior art methods in terms of cost,reliability, selectivity, yield and throughput. Specific advantages forparticular process steps are discussed below.

The 3-aryl-5-haloalkyl pyrazoles prepared by the methods of the presentinvention may be used to provide outstanding control of broadleaf andnarrowleaf weeds such as gallium, blackgrass, pigweed, cocklebur,velvetleaf and hemp sesbania in various crops such as corn, soybean,wheat, barley, rice and nuts. They are also effective in forestryagainst undesirable trees and vines. The 3-aryl-5-haloalkyl pyrazolesmay be applied in a variety of application modes and may be used asherbicidal compositions, as co-herbicides, or in combination withsafeners, fungicides, insecticides, nematicides and/or other diseasecontrol agents. The herbicidal compound prepared according to thepreferred embodiment of the invention, isopropyl 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate,is especially effective for preemergent control of broadleaf andnarrowleaf weeds associated with small-grain crops such as wheat.

As used herein, the terms "alkyl", "alkenyl", or "alkynyl", whether usedalone or in compound form (e.g., haloalkyl, alkoxy, alkoxyalkyl, etc.),refers to both linear and/or branched-chain moieties. Representative,non-limiting alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,cycloalkenyl and cycloalkenylalkyl members include the following:methyl, ethyl, the isomeric propyls, butyls, pentyls, hexyls, heptyls,octyls, nonyls, decyls, etc.; vinyl, allyl, crotyl, methallyl, theisomeric butenyls, pentenyls, hexenyls, heptenyls, octenyls; ethynyl,the isomeric propynyls, butynyls, pentynyls, hexynyls, etc.; the alkoxy,polyalkoxy, alkoxyalkyl and polyalkoxyalkyl analogs of the foregoingalkyl groups, e.g., methoxy, ethoxy, propoxys, butoxys, pentoxys andhexoxys and corresponding polyalkoxys and alkoxyalkyls, e.g.,methoxymethoxy, methoxyethoxy, ethoxymethoxy, ethoxyethoxy,methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, propoxymethyl,isopropoxymethyl, butoxymethyl, isobutoxymethyl, tertbutoxymethyl,pentoxymethyl, hexoxymethyl, etc., cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclopropylmethyl, cyclobutylmethyl,cyclopentylmethyl, etc.; the isomeric cyclopentenes, cyclohexenes andcycloheptenes having mono- or di-unsaturation; representative aryl,aralkyl and alkaryl groups include phenyl, the isomeric tolyls andxylyls, benzyl, naphthyl, etc.

The term "haloalkyl" refers to alkyl radicals substituted with one ormore halogen (chloro, fluoro, bromo or idodo) atoms. Polyhaloalkylmembers may have the same or mixed types of halogen atoms. A"perhaloalkyl" refers to an alkyl in which each of the hydrogen atoms issubstituted with halogen atoms. A haloalkyl which is "fully halogenated"at a particular carbon atom has halogen atoms in place of all thehydrogen atoms normally bonded to that carbon. Representative mono-, di-and tri-haloalkyl members include: chloromethyl, chloroethyl,bromomethyl, bromoethyl, iodomethyl, iodoethyl, chloropropyl,bromopropyl, iodopropyl, 1,1,-dichloromethyl, 1,1dibromomethyl,1,1-dichloropropyl, 1,2-dibromopropyl, 2,3-dibromopropyl,1-chloro-2-bromoethyl, 2-chloro-3-bromopropyl, trifluoromethyl,trichloromethyl, etc.

The term "heterocyclic" as used herein refers to a closed-ring structurein which one or more of the atoms in the ring is other than carbon.Exemplary heterocyclic members include: alkylthiodiazolyl; piperidyl;piperidylalkyl; dioxolanylalkyl, thiazolyl; alkylthiazolyl;benzothiazolyl; halobenzothiazolyl; furyl; alkyl-substituted furyl;furylalkyl; pyridyl; alkylpyridyl; alkyloxazolyl; tetrahydrofurylalkyl;3-cyanothienyl; thienylalkyl; alkyl-substituted thienyl;4,5-polyalkylene-thienyl; piperidinyl; alkylpiperidinyl; pyridyl; di- ortetrahydropyridinyl; alkyltetrahydromorpholyl; alkylmorpholyl;azabicyclononyl; diazabicycloalkanyl, benzoalkylpyrrolidinyl;oxazolidinyl; perhydrooxazolidinyl; alkyloxazolidyl; furyloxazolidinyl,thienyloxazolidinyl, pyridyloxazolidinyl, pyrimidinyloxazolidinyl,benzooxazolidinyl, C₃₋₇ spirocycloalkyloxazolidinyl, alkylaminoalkenyl;alkylideneimino; pyrrolidinyl; piperidonyl; perhydroazepinyl;perhydroazocinyl; pyrazolyl; dihydropyrazolyl; piperazinyl;perhydro-1,4-diazepinyl; quinolinyl, isoquinolinyl; di-, tetra- andperhydroquinolyl- or -isoquinolyl; indolyl and di- and perhydroindolyl,etc.

The processes of the present invention are preferably employed toprepare 3-aryl-5-haloalkyl pyrazole compounds of Formula I, ##STR27##wherein R¹ is C₁₋₅ alkyl, R² is C₁₋₃ haloalkyl, R³, R⁵ and R⁶ arehalogen and R¹⁰ is C₁₋₅ alkyl. The haloalkyl R² is preferably fullyhalogenated at the carbon nearest the pyrazole ring. In a most preferredembodiment, the processes are used to prepare isopropyl 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate,structurally represented as the compound of Formula II, ##STR28## Thepreparation of the aryl-pyrazole of Formula II is generally set forth asdescribed below for compounds of Formula I, and is further exemplifiedin Example 1. In the process steps described below, the various symbolsdefining radical substituents (e.g. R¹, R², etc.) have the same meaningas defined for the compounds of Formula I, unless otherwise indicated.

A preferred overall process for producing compounds of Formula I startswith substituted acetophenones of Formula Ia, ##STR29## which may beconverted to compounds of Formula I through a series of process steps (Athrough E) which effect the following conversions: ##STR30## Process A

Process A relates to the acylation of acetophenones to formphenyl-diketones. While the acetophenones used in the acylation stepare, as described below, preferably 2,4-dihalo-5-methyl-acetophenones,the present invention encompasses using acetophenones in which thephenyl moiety is unsubstituted or has other substituents. In the generalcase, an acetophenone of the Formula IIIa may be converted to aphenyl-diketone of the Formula IIIb according to the reaction: ##STR31##wherein Ar is phenyl or substituted phenyl and R² is a C₁₋₃ haloalkyland is fully halogenated at the carbon which is nearest the carbonylonce the phenyl-diketone is formed.

As used herein, the term "substituted phenyl" refers to a radical havingthe Formula Ar-1, ##STR32## wherein R⁴ is selected from the groupconsisting of: C₁₋₈ alkyl; C₃₋₈ cycloalkyl, cycloalkenyl,cycloalkylalkyl or cycloalkenylalkyl; C₂₋₈ alkenyl or alkynyl; benzyl;the aforementioned members substituted with halogen, amino, nitro,cyano, hydroxy, alkoxy, alkylthio, ##STR33## --YR⁸, or --NR⁸ R⁹ ;mercaptoalkyl; alkoxyalkyl or polyalkoxyalkyl; carbamyl; amino, nitro orcyano; halogen; hydroxy; C₁₋₁₀ heterocycle containing O, S(O)_(m) and/orNR⁸ heteroatoms; C₆₋₁₂ aryl, aralkyl, or alkaryl; ##STR34## --YR⁸, or--NR⁸ R⁹ ; and two or more of the aforementioned R⁴ members combinedthrough a linking group to form a cyclic ring having up to 9 ringmembers which may be substituted with any of the R⁴ members, the linkinggroup including saturated or unsaturated carbon, --(C═X)--, hetero Ohetero S(O)_(m), and hetero NR⁸ ; X is O, S(O)_(m), NR⁸, or CR⁸ R⁹ ; Yis O, S (O)_(m), NR⁸ ; m is 0-2; n is 1-5; and R⁸ and R⁹ are selectedfrom the group consisting of: hydrogen; C₁₋₈ alkyl; C₃₋₈ cycloalkyl,cycloalkenyl, cycloalkylalkyl or cycloalkenylalkyl; C₂₋₈ alkenyl oralkynyl; benzyl; the aforementioned members substituted with halogen,amino, nitro, cyano, hydroxy, alkoxy, alkylthio; thioalkyl; alkoxyalkyl;polyalkoxyalkyl; carbamyl; halogen; amino; nitro; cyano; hydroxy; C₁₋₁₀heterocycle containing O, S (O)_(m) and/or N heteroatoms; C₆₋₁₂ aryl,aralkyl, or alkaryl; and two or more of the aforementioned memberscombined through a linking group to form a cyclic ring having up to 9ring members which may be substituted with any of the members, thelinking group including saturated or unsaturated carbon, --(C═X)--,hetero O, hetero S(O)_(m), and hetero N.

The substituted phenyl of the present invention more preferably includescompounds of the Formula Ar-2, ##STR35## wherein: R⁵ is hydrogen orhalogen, R⁶ is hydrogen, halogen, nitro, cyano or YR⁸, R⁷ is hydrogen,lower alkyl, haloalkyl, ##STR36## wherein X is O, S(O)_(m), NR⁸ or CR⁸R⁹ ; Y is O, S(O)_(m) NR⁸ ; m is 0-2; and R⁸ and R⁹ are as defined forFormula Ar-1. In a still more preferred embodiment, R⁵ is halogen, R⁶ is##STR37## halogen, R⁷ is lower alkyl, haloalkyl, or where W is hydrogen,hydroxy, halogen, or --OC₁₋₅ alkyl.

The acetophenones of Formula IIIa are known in the art. For example,2,4-dihalo-5-methyl-acetophenones of Formula Ia may be prepared fromcommercially available 2,4-dihalogenated toluene. Briefly, thesubstituted toluene may be acylated using an acylating agent such as anacyl halide, an anhydride or a ketene in the presence of a Lewis acid orBronstead acid at temperatures ranging from about -50° C. to about 200°C. and preferably from about 0° C. to about 100° C. The amount ofacylating agent preferably ranges from one molar equivalent to anexcess, and preferably an excess of about 2 molar equivalents relativeto the amount of substituted toluene. The acylation reaction may becarried out neat or in any inert solvent. Prefered solvents includenitrobenzene, carbon disulfide, organic acids or halogenatedhydrocarbons. The reaction may be carried out under pressure, withpressures ranging from about 1×10⁵ Pa (about 1 psig) to about 1.7×10⁵ Pa(about 10 psig). Reaction time varies depending on reagentconcentrations, temperature, etc. The preparation of phenyl-diketones ofFormula IIIb from such acetophenones may be carried out substantially asdescribed below for preparing compounds of Formula Ib and Formula IIb.

In a more preferred process, phenyl-diketones of Formula Ib are preparedfrom acetophenones of Formula Ia according to the reaction ##STR38##wherein R² is C₁₋₃ haloalkyl and R⁵ and R⁶ are halogen, by acylating acompound of Formula Ia with an acylating agent. A suitable acylatingagent is a haloacylhalide structurally represented as the compound ofFormula A1, ##STR39## wherein Z is halogen and R² is C₁₋₃ haloalkyl. Thehaloacylhalide preferably has a fully halogenated α-carbon, such thatafter acylation and after subsequent formation of the pyrazole ring, theR² carbon nearest the pyrazole ring is fully halogenated. The completehalogenation of this carbon favorably affects the herbicidal activity ofcompounds of Formula I. Moreover, the full halogenation of this R²carbon also facilitates synthesis of the desired regioisomer, as notedbelow (Process B). The haloacylhalide is preferably a haloacetylhalide,more preferably a trihaloacetylhalide, even more preferably atrihaloacetylchloride and most preferably trifluoroacetylchloride.(Example 1, Process A). Another suitable acylating agent is an alkylhaloacetate, with alkyl trihaloacetates being preferred and methyl orethyl trifluoroacetate being most preferred. Haloacylhalides and alkylhaloacetates are equally preferred as acylating agents in terms ofreactivity or yield, but the use of haloacylhalides presently offer acost advantage over alkyl trihaloacetates.

Compounds of Formula Ib may be prepared in any anhydrous solvent ormixture of solvents, including ether, alcohols, dimethylsulfoxide,toluene, benzene, etc, with alcohol being a preferred solvent. Thereaction is preferably carried out in the presence of a strong base suchas an alkali alkoxide, alkali amide or alkali hydride, with alkalialkoxides such as sodium methoxide being preferred. The use ofalcohol/alkali alkoxide solvent mixtures generally results in betteryields, and higher substrate payloads.

Preferably, a slight excess of acylating agent (1.2 to 1.5 molarequivalents relative to the amount of acetophenone to be reacted) ispremixed with an excess of a 75% methanol/25% sodium methoxide solution(about 1.5 molar equivalents of sodium methoxide relative to the amountof acetophenone) to form a reagent mixture. To accommodate theexothermic mixing, the initial temperature of methanol/sodium methoxidesolution, prior to mixing, ranges from about -20° C. to about 60° C.,more preferably from about -10° C. to about 20° C. and is mostpreferably about -5° C. The temperature is controlled during the mixingand before addition of the acetophenone to be less than about 60° C. andmore preferably less than about 40° C. The substituted acetophenone isthen added to the reagent mixture, followed by the further addition ofmethanol/sodium methoxide solvent (another 1.5 molar equivalentsrelative to the amount of acetophenone). The reaction proceeds atatmospheric pressure and at temperatures ranging from about 25° C. toabout 75° C., more preferably from about 50° C. to about 70° C. and mostpreferably at about 60° C. The reaction time varies from about a fewminutes to several days, depending primarily on the concentration of thereagents and the reaction temperature. Yields of greater than about 90%are typically achieved using reaction times of about 45 minutes at 60°C.

While the haloacylhalide is preferably premixed with the alkoxide /alcohol solution prior to adding the acetophenone substrate, the orderof combining the acylating agent, substrate, and solvent or solventmixture is not narrowly critical. For example, the reaction could alsobe effected by premixing the acetophenone substrate with a basic solventand then adding the acylating agent, or as a further alternative, byadding the acylating agent and acetophenone at the same time. Oneconsideration in determining a preference of order relates tocontrolling exotherms which result upon combination of reagent,substrate and solvents.

Upon completion of the reaction, the compound of Formula Ib may, ifdesired, be isolated and/or purified. The resulting compound isprecipitated out of solution by cooling the reaction mixture to about50° C., neutralizing with a mineral acid solution such as a 10% Hclsolution, and further cooling to about 10° C. The precipitated productcan then be isolated by filtration, and, if desired, purified by methodsknown in the art, such as crystallization.

Where the phenyl-diketone of Formula Ib will be subsequently used inProcess B, however, several alternative work-up schemes may be suitablyemployed to replace the solvent system used in Process A (e.g.alcohol/alkali alkoxide) with the system to be subsequently used inProcess B (e.g. aromatic solvents). For example, the compound of FormulaIb may be precipitated and isolated as described above, and the isolatedphenyl-diketone precipitate can be reslurried into the solvent to beused for Process B, without further drying or purification. Morepreferably, the reaction mixture is worked up without isolating thephenyl-diketone product. Where an alcohol/alkali alkoxide solvent is tobe replaced with an aromatic solvent, the work-up preferably includesneutralizing the reaction mixture with a mineral acid solution as a 10%Hcl solution and stripping the alcohol at temperatures ranging fromabout 45° C. to about 50° C. under a slight vacuum. At least about 50%of the alcohol should be removed, preferably at least about 80% isremoved and most preferably at least about 90% is removed. The aromaticsolvent is then added and the aqueous layer is removed. A variation ofthis method includes first stripping the alcohol under reduced pressure,cooling the reaction mixture to about ambient temperature, adding thearomatic solvent, washing with an aqueous mineral acid solution, furtherwashing with deionized water and removing the resulting aqueous phase.In either of the latter two aforementioned work-up schemes, the organicphase contains the desired phenyl-diketone product and is used inProcess B, as described below.

In a most preferred embodiment, a phenyl-diketone of Formula IIb isprepared from an acetophenone of Formula IIa according to the reaction:##STR40## This reaction is carried out substantially as described abovefor preparing compounds of Formula Ib, using eithertrifluoroacetylchloride, methyl trifluoroacetate or ethyltrifluoroacetate as the acylating agent. Trifluoroacetylchloride ispresently less expensive than methyl or ethyl trifluoroacetate, and istherefore preferred with respect to cost, but the aforementionedacylating agents are otherwise equally preferred. The preparation ofcompounds of Formula IIb is further exemplified in Example 1 (ProcessA).

Process B

Process B relates to the cyclization of phenyl-diketones and subsequentalkylation to form alkylated 3(5)-aryl-5(3)-haloalkyl pyrazoles. In thegeneral case, an aryl-pyrazole of Formula IIIb may be converted to analkylated 3-aryl-pyrazole of Formula IIId according to the reaction##STR41## wherein: Ar is phenyl or substituted phenyl as defined forProcess A; R¹ is alkyl or alkyl substituted with halogen, amino, nitro,cyano, hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio; andR² is alkyl, hydroxy, alkoxy, acyl, carboxylic acid and aldehyde, amideand ester derivatives thereof, halogen, haloalkyl, amino, nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl. R¹ is preferably C₁₋₅ alkyl and R² is preferably aC₁₋₃ haloalkyl. This reaction is effected by condensing a compound ofFormula IIIb with hydrazine and preferably with an excess of hydrazine,removing any excess hydrazine, and alkylating, as described in detailbelow for preparing compounds of Formula Id and IId. If desired, anintermediate compound of the Formula IIIc ##STR42## wherein Ar and R²are as defined above for compounds of Formulae IIIb and IIId, may beformed by condensing the phenyl-diketone of Formula IIIb under acidicconditions or adding an acid to the reaction mixture after thecondensation. The alkylation reaction may be carried outregioselectively, under acidic conditions, without deprotonating theN-hydrogen of Formula IIlc, to form the 3-aryl-isomer of Formula IIIe,##STR43## wherein Ar and R¹ are as defined above for compounds ofFormulae IIIb and IIId and wherein R² is alkyl, hydroxy, alkoxy, acyl,carboxylic acid and aldehyde, amide and ester derivatives thereof,halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl.

Process B particularly relates to the regioselective preparation of3-aryl-5-haloalkyl pyrazoles of Formula Id according to the overallreaction: ##STR44## wherein R¹ is C₁₋₅ alkyl, R² is C₁₋₃ haloalkyl andR⁵ and R⁶ are halogen. A phenyl-diketone of Formula Ib is condensed withhydrazine in a reaction mixture to form one or more intermediates,discussed in detail below and collectively referred to asalkyl-pyrazole-precursor intermediates. An alkylating agent is thenadded to the reaction mixture and reacts with thealkyl-pyrazole-precursor intermediate(s) to form, in the general case, amixture of two isomers, collectively represented by Formula Ic,##STR45## Advantageously, when the alkylation reaction is carried outunder acidic conditions and/or with an electron withdrawing moiety asthe R² group, the predominant product formed is the1-alkyl-3-aryl-5-haloalkyl-pyrazole (Formula Id) rather than the1-alkyl-5-aryl-3-haloalkyl-pyrazole, referred to hereinafter as the3-aryl isomer and the 5-aryl isomer, respectively.

The hydrazine is preferably unsubstituted hydrazine. Whilealkyl-substituted hydrazines such as methyl-hydrazine could be used inthe present invention to form an alkylated pyrazole in a single step,the regioisomer resulting therefrom is predominantly the 5-aryl isomerrather than the desired 3-aryl isomer. Hydrazine may be reacted with thephenyl-diketone of Formula Ib in any suitable solvent or mixture ofsolvents, including both organic and aqueous solvents. Based onavailability and cost, hydrazine is preferably used in the reaction asan aqueous solution. To facilitate subsequent work-up steps, thephenyl-diketone is preferably in an organic solution. Aromatic solventshaving a relatively high boiling point such as toluene, xylene, cymene,cumene and ethyl benzene are preferred, with toluene being a mostpreferred solvent for the phenyl-diketone.

The reaction is most preferably effected by adding an aqueous hydrazinesolution to a toluene solution containing the phenyl-diketone to form atwo-phase reaction mixture in which the phenyl-diketone is in an organicphase and hydrazine in an aqueous phase. The toluene solution ispreferably at about ambient temperature when the hydrazine solution isadded. Sufficient hydrazine solution is added to provide astoichiometric excess amount of hydrazine in the reaction mixturerelative to the phenyl-diketone. For purposes herein, the stoichiometricexcess amount is the residual amount of hydrazine which would remainafter all of the phenyl-diketone has completely reacted with hydrazine.Equivalently, the stoichiometric excess amount of hydrazine in thereaction mixture or reaction zone at any given time is the differencebetween the molar amount of hydrazine present at that time and the molaramount of phenyl-diketone present at that time. The amount of excesshydrazine present in the reaction mixture is preferably at least about 1mole percent of a reference amount, the reference amount being the sumof the molar amount of unreacted phenyl-diketone and the molar amount ofalkyl-pyrazole-precursor intermediate formed. The amount of excesshydrazine is more preferably at least about 15 mole percent of thereference amount, and is most preferably about 20 mole percent of thereference amount. While upper limits are not narrowly critical, theamount of excess hydrazine preferably ranges from about 5 to about 50mole percent and more preferably from about 10 to about 25 mole percent.The use of excess hydrazine maximizes the conversion of thephenyl-diketone to alkyl-pyrazole-precursor intermediate, therebyresulting in improved yields. After adding the hydrazine solution, thereaction mixture is stirred to facilitate the inter-phase reactionbetween hydrazine and the phenyl-diketone. The reaction mixture may alsocontain some unreacted acetophenone carried over from the previous step(Process A). The reaction is preferably effected at atmospheric pressureand at temperatures ranging from about 0° C. to about 60° C., morepreferably at temperatures ranging from about 30° C. to about 50° C. andmost preferably at a temperature of about 40° C. Reaction times varyfrom about a few minutes to several days depending on the concentrationof the reagents and the reaction temperature. At 40° C., the reaction iscompleted, as determined by gas chromatography, within about 30 minutes.

Without being bound by theory, one or more intermediate compounds arebelieved to result from condensation of the phenyl-diketone (Formula Ib)with hydrazine. For example, 3-aryl-5-hydroxy-pyrazolines of Formula B1or 3(5)-aryl-pyrazoles of Formula B2 ##STR46## are likely to form,depending on the reaction conditions employed. Compounds of Formula B1are thought to be the predominant intermediate when the condensationreaction is carried out under neutral conditions, whereas compounds ofFormula B2 are thought to predominate under acidic conditions. Hence,while it is not necessary to isolate and/or characterize thealkyl-pyrazole-precursor intermediate compounds for purposes of thepresent invention, aryl-pyrazole intermediates of Formula B2 may beobtained by allowing the aforementioned condensation reaction to proceedunder acidic conditions (e.g. using an acetic acid solvent as in Example2) or, alternatively, by adding acid to the reaction mixture after thecondensation reaction is completed. Regardless of the exact structure ofthe intermediate(s) formed as the condensation reaction proceeds, thephenyl-diketone reagent and the resulting intermediate(s) remainpreferentially in the organic phase of the reaction mixture, whilehydrazine remains in the aqueous phase thereof. However, some resultingintermediate may precipitate out of solution.

Upon completion of the condensation reaction, the excess hydrazine andthe resulting alkyl-pyrazole-precursor intermediates are preferablyseparated from each other before alkylating the intermediates to formalkylated pyrazole compounds of Formulas Ic or Id. Such separationminimizes the explosive danger which would exist if the resultingintermediate(s) were alkylated in the presence of hydrazine. Theseparation may be effected by any means known in the art, but ispreferably effected by phase separation (in two-phase reaction mixtures)or by liquid-liquid solvent extraction methods (in single-phase reactionmixtures). Excess hydrazine is preferably removed from the reactionmixture without isolating the resulting intermediate(s). Where thereaction mixture is the preferred two-phase system described above, theexcess hydrazine is removed from the reaction mixture by first heatingthe reaction mixture to redissolve into the organic phase any amount ofprecipitate which may have formed during the reaction. Such heating alsofacilitates separation of the aqueous phase from the organic phase intoseparate aqueous and organic layers. If desired, other solvents may beadded to the two-phase system to either increase the partitioncoefficients or sharpen phase separation. The aqueous phase layer, whichincludes hydrazine, is then removed from the reaction mixture. Theremaining organic phase may be further washed with an aqueous solution,such as a brine (NaCl) solution. This wash solution is also separatedand removed from the organic solution. In an alternative two-phasesystem, the resulting intermediate(s) and the excess hydrazine may beseparated from each other by removing organic phase containing theresulting intermediate(s) from the reaction mixture. Alternatively, thereaction can be carried out in a single-phase organic system, in whichanhydrous hydrazine is reacted with a phenyl-diketone of Formula Ib andthe excess hydrazine is removed by extraction with water. If thereaction is instead carried out in a single phase aqueous solution, theresulting intermediate(s) may be separated by extraction with an organicsolvent. The phase separation and liquid-liquid extraction work-up stepsdescribed herein are less cumbersome than isolation or purificationtechniques (e.g. precipitation and/or crystallization) and safer thandistillation methods.

After condensing the phenyl diketone (Formula Ib) with hydrazine andremoving any excess hydrazine, an alkylating agent is added to thereaction mixture to alkylate the alkyl-pyrazole-precursorintermediate(s). The resulting alkylated pyrazole is representedgenerally by Formula Ic. Suitable alkylating agents include alkylhalides, alkyl sulfonates and mono- or di-alkylsulfates, withdialkylsulfates being preferred. When R¹ is a methyl group,dimethylsulfate, methyliodide, and methylbromide are preferredalkylating agents. Dimethylsulfate should be used in at least anequimolar amount relative to the phenyl-diketone of Formula Ib, as thesecond methyl group is not reactive enough to alkylate theintermediate(s). The alkylating agents are preferably added to thereaction mixture in molar excess relative to the amount phenyl-diketonebeing reacted, the molar excess ranging from about 1.01 to about 1.3molar equivalents, more preferably from about 1.05 to about 1.25 molarequivalents and most preferably from about 1.1 to about 1.2 molarequivalents. The alkylating agents should generally be added slowly tothe reaction mixture to help avoid large exothermic excursions.

While the alkylation could be carried out under neutral, basic or acidicconditions, acidic conditions are preferred to maximize theregioselective preparation of the desired 3-aryl isomer of Formula Id.(Example 3). Significantly, the percentage of the 3-aryl isomer obtainedunder acidic conditions is consistently greater than about 90% of thetotal amount of aryl-pyrazole product, and frequently greater than about95%, whereas under non-acidic conditions, the percentage of 3-arylisomer obtained ranged from about 55% to about 80%. Without being boundby theory, this selectivity is believed to arise from the fact thatintermediates such as the compound of Formula B2 exist predominantly(greater than about 90%) in the 5-aryl tautomeric form (Formula B3) andonly marginally (less than about 10%) in the 3-aryl form (Formula B4):##STR47## Under basic conditions, the nitrogen is believed to bedeprotonated, leaving a very reactive electron pair for alkylation.Since the deprotonated nitrogen is predominantly the nitrogen closest tothe aryl group, the 5-aryl isomer dominates under basic conditions. Incontrast, when the alkylation is carried out under acidic conditions, nodeprotonation occurs and the other nitrogen (ie, the nitrogen lackinghydrogen) is relatively more reactive. Hence, the alkylation isselective to form the 3-aryl isomer under acidic conditions. Acidicconditions are also preferred over basic conditions with regard to thestability of the reaction for particular R² constituents, such as CF₂Cl. (Example 4).

The selective preparation of the 3-aryl isomer is also favorablyinfluenced by the electron-withdrawing capability of the R² group.Electron withdrawing R² moieties which enhance selective alkylationinclude substituted alkyl, acyl, carboxylic acid and aldehyde, amide andester derivatives thereof, halogen, haloalkyl (Example 3), nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl. The R² group is preferably a haloalkyl group andmost preferably a haloalkyl group which is fully halogenated at thecarbon closest to the pyrazole ring. The aryl group has relativelylittle effect on regioselectivity.

Preferred solvents for the alkylation reaction include toluene, xylene,cymene, acetone, dimethylsulfoxide, dimethylformamide, dioxane, etc,with toluene being most preferred. The alkylation is most preferablyeffected by reacting the intermediate(s) with a dialkylsulfate inanhydrous toluene under reflux conditions. The toluene solvent may beneutral prior to the reaction, but acidic conditions are immediatelygenerated as the alkylation reaction proceeds under reflux. For example,where dimethylsulfate is used as the alkylating agent, methyl-sulfonicacid is generated as soon as methylation of the intermediate(s) begins.Alternatively, to ensure acidic conditions before the start of thereaction, a small amount of acid such as p-toluene sulfonic acid can beadded. The reaction is preferably carried out under atmospheric pressureand at a temperature ranging from about 60° C. to about 120° C., andmost preferably at about 105° C. As the alkylation reaction proceeds,water is removed from the reaction mixture as a toluene/water azeotrope.The azeotrope is preferably condensed and the condensate separated, withthe toluene being returned to the reaction mixture. The progress of thereaction may be monitored using gas chromatography, and, if necessary,additional alkylating agent may be added to effect complete conversionto the alkylated pyrazole. Reaction times may range from about a fewminutes to several days depending on the concentration of the reagentsand the reaction temperature. Overall yields ranging from about 70% toabout 85% are typically achieved using reaction times of about 16 hoursat a temperature of about 105° C.

After the reaction is completed, the product may be isolated andpurified by methods known in the art, including precipitation andfiltration, concentration, extraction, crystallization orchromatographic methods. The reaction product mixture is preferablyworked up by cooling to about 50° C. and then washing in succession withcaustic solutions (5% NaOH, then 10% NaOH) to destroy any excessdimethylsulfate and to neutralize the organic phase. The product mixtureis then further washed with a brine solution (10%). The toluene solventis then replaced with methanol by stripping toluene in vacuo and addingmethanol. The 3-aryl regioisomer is isolated by adding water (16:1methanol:H₂ O), cooling to a temperature of about 5° C. to about 10° C.,and centrifuging to crystallize the desired 3-aryl isomer while leavingthe undesired 5-aryl isomer in solution.

In a most preferred embodiment, the alkylated 3-aryl-pyrazole of FormulaIId is prepared from the phenyl diketone of Formula IIb according to thereaction: ##STR48## This reaction is carried out substantially asdescribed above for preparing compounds of Formula Id, and is furtherexemplified in Example 1 (Process B).

Process C

Process C relates to the oxidation of alkyl-substituted benzenecompounds to form the corresponding benzoic acids. While the substratefor this reaction is preferably a 2,4-dihalo-5-pyrazole toluene, theoxidation method of the present invention is more generally applicableto other alkyl-substituted benzene substrates, including for example,unsubstituted toluene, substituted toluene, substituted toluene where atleast one substituent is a substituted or unsubstituted heterocyclicring having up to 6 ring members, and substituted toluene where at leastone substituent is pyrazole or substituted pyrazole. In particular, theoxidization method of the present invention may be used to prepare asubstituted-benzoic acid pyrazole of Formula IIIg from asubstituted-toluene of Formula IIIf according to the reaction ##STR49##wherein in the above formulae, R⁵ and R⁶ are halogen and Pyr is asubstituted or unsubstituted pyrazole.

The term "substituted pyrazole" as used herein means a substitutedpyrazole of Formula Pyr-1, ##STR50## wherein in the above formula, R¹ ishydrogen, alkyl or alkyl substituted with halogen, amino, nitro, cyano,hydroxy, carboxy, alkoxy, thio, mercaptoalkyl or alkylthio; R² is alkyl,hydroxy, alkoxy, acyl, carboxylic acid and aldehyde, amide and esterderivatives thereof, halogen, haloalkyl, amino, nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl; and R³ is hydrogen or halogen. The substitutedpyrazole is more preferably the 1-alkyl-5-aryl isomer of Formula Pyr-2,##STR51## wherein in the above formula, R¹ is hydrogen or C₁₋₅ alkyl; R²is hydrogen or C₁₋₃ haloalkyl; and R³ is hydrogen or halogen.

Substituted-toluenes of Formula IIIf are oxidized to form benzoic acidsof Formula IIIg substantially as detailed below for preparing compoundsof Formula Ie and IIe.

In a preferred embodiment of Process C, benzoic acid compounds ofFormula Ie are prepared by oxidizing 2,4-dihalo-5-pyrazole-toluenecompounds of Formula Id according to the reaction: ##STR52## wherein R¹is C₁₋₅ alkyl, R² is C₁₋₃ haloalkyl, and R⁵ and R⁶ are halogen. Thereaction is preferably carried out as a direct oxidation by reacting thecompound of Formula Id with molecular oxygen in the presence of metalsalt catalyst or mixtures thereof, catalyst promoter and free radicalinitiator. As detailed below, the use of benzoyl peroxide as theinitiator of this reaction provides for a more robust and reliablereaction relative to prior art initiators.

A variety of metal salt catalysts such as cobalt salts, manganese salts,nickel salts, cesium salts and zirconium salts may be used individuallyor in combination. Examples of such salts include cobalt (II) acetate,cobalt formate, cobalt hexylate, cobalt chloride, cobalt carbonate,cobalt acetylacetonate, manganese (II) acetate, manganese chloride,cesium (III) acetate, zirconium (IV) acetylacetonate, zirconiumchloride, nickel chloride, etc. Cobalt acetate, Co(OAc)₂, manganeseacetate, Mn(OAc)₂ or co-catalysts thereof are preferred catalysts. Thetotal amount of a single catalyst or of a combination of catalysts in amixture can range from about less than 1% to about 100% molarequivalents relative to the compound of Formula Id.

A catalyst promoter is used in conjunction with the metal salt catalyst.Preferred catalyst promoters include alkyl halides, halide salts,lithium salts, carboxylate salts, with halide salts such as alkalihalides and ammonium halides being more preferred. Bromide compoundssuch as sodium bromide, hydrogen bromide and ammonium bromide are mostpreferred as catalyst promoters. The amount of halide salt promoterpreferably ranges from about 0.1 mole % to about 10 mole % relative tothe compound of Formula Id. A ketone such as acetone may be used as acatalyst promoter or as a co-promoter with the halide salt promoter.Without being bound by theory, it appears that acetone hastens thetypically slow induction period of the reaction, thereby shortening thetotal reaction time by as much as 20% to 30%.

While any known initiator, such as hydrogen peroxide, is suitable toinitiate the oxidation reaction, benzoyl peroxide is a preferredinitiator. Advantageously, the use of benzoyl peroxide makes thereaction more robust, dependable and reliable relative to the use ofhydrogen peroxide, which is substantially less reliable and oftenerratic with regard to initiating the oxidation. Without being bound bytheory, it is believed that the benzoyl peroxide makes the reaction lesssensitive to impurities which commonly stall the reaction. The amount ofbenzoyl peroxide used preferably ranges from about 0.1 mole % to about10 mole % relative to the substituted toluene compound of Formula Id,more preferably from about 0.1 mole % to about 5 mole % and mostpreferably from about 0.3 mole % to about 0.7 mole %.

The reaction is preferably carried out in any suitable solvent whichdoes not interfere with the course of the reaction; however, thereaction can also be carried out neat. Preferred solvents includealiphatic carboxylic acids and anhydrides such as acetic acid and aceticanhydride. Acetic acid is a most preferred solvent.

The substrate compound of Formula Id is preferably combined with thecatalyst, promoter and initiator in a suitable reactor and mixed. A mostpreferred reaction mixture includes the substrate and the followingcombination of co-catalysts, catalyst promoters and initiator in aceticacid: from about 0.9 to about 1.1 mole percent Co(OAc)₂, from about 0.09to about 0.11 mole percent Mn(OAc)₂, from about 2.7 to about 3.3 molepercent sodium bromide, from about 4.5 to about 5.5 mole percent acetoneand from about 0.6 to about 0.8 mole percent benzoyl peroxide. Molecularoxygen is supplied to the reaction mixture in stoichiometric excess aspure O₂, as air, or as a mixture of oxygen or air in other gasses.Without being bound by theory, the rate of reaction appears to be masstransfer limited. As such, the mixture should be well mixed or agitatedduring the reaction to maximize oxygen dispersion. The reaction mayproceed at atmospheric pressure, or, if desired, in a pressurizedatmosphere. When oxygen is used in a pressurized system, the oxygenpressure preferably ranges from about 1×10⁵ Pa to about 70×10⁵ Pa (about1 atm to about 1000 psig) and more preferably from about 1×10⁵ Pa toabout 18×10⁵ Pa (about 1 atmosphere to about 250 psig). The oxygenpressure is most preferably about 1.7×10⁵ Pa (about 10 psig). When airis used, the above-recited pressure values represent the partialpressure of oxygen in the air. While higher pressures favorablyinfluence the reaction rate, the capital costs required to effect suchpressurization may negate any overall benefit to conducting the reactionat higher pressures. The reaction preferably proceeds at temperaturesranging from about 80° C. to the boiling point of the solvent. Whenacetic acid is used as the solvent, the reaction temperature preferablyranges from about 80° C. to about 120° C., with a temperature of about110° C. being preferred. Reaction times may range from about a fewminutes to several days depending on the concentration of the reagentsand the reaction temperature. Yields of about 90% are typically achievedin about 5 to 50 hours at a temperature of about 110° C.

After the reaction is completed, the product may be isolated andpurified using conventional methods. However, where the resultingbenzoic acid of Formula Ie will be used in subsequent steps of theoverall process, the product is preferably not isolated from solutionprior to the next step (Process D). When use in the subsequent step isanticipated, the reaction mixture is kept at a temperature of greaterthan about 70° C. to minimize the potential for product precipitation.

In a most preferred embodiment, the benzoic acid of Formula IIe isprepared from the aryl-pyrazole of Formula IId according to thereaction: ##STR53## This reaction is carried out substantially asdescribed above for preparing compounds of Formula Ie, and is furtherexemplified in Example 1 (Process C). In this reaction, the methyl groupon the aryl member of Formula IId is oxidized preferentially relative tothe methyl on the pyrazole member. Typically, only about 1-2% of theproduct has the methyl group on the pyrazole oxidized. To preventfurther oxidation of the pyrazole-methyl, however, the reaction shouldbe discontinued once all of the aryl-methyl has been reacted. Forexample, once all of the substrate compound has reacted, as determinedby HPLC sampling, the reaction may be terminated by cutting off oxygensupply and, if the system is pressurized, venting the reactor.

Process D

Process D relates to the halogenation of heterocyclic compounds. Whilethe substrate for this reaction is preferably a1-alkyl-3-aryl-5-haloalkylpyrazole, the bromination method of thepresent invention is more generally applicable to other heterocyclicsubstrates, including heterocyclic compounds having up to 6ring-members, unsubstituted pyrazoles, or substituted pyrazoles. Inparticular, the bromination method of the present invention may be usedto prepare a phenyl-substituted pyrazole of Formula IIIh from a compoundof Formula IIId according to the reaction ##STR54## wherein: Ar isphenyl or substituted phenyl as defined in Process A; R¹ is hydrogen,alkyl or alkyl substituted with halogen, amino, nitro, cyano, hydroxy,carboxy, alkoxy, thio, mercaptoalkyl or alkylthio; and R² is alkyl,hydroxy, alkoxy, acyl, carboxylic acid and aldehyde, amide and esterderivatives thereof, halogen, haloalkyl, amino, nitro, cyano,mercaptoalkyl, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylphosphinylor alkylphosphonyl. More preferably, R¹ is hydrogen or C₁₋₅ alkyl and R²is C₁₋₃ haloalkyl. The bromination of such substrates is carried outsubstantially as described below for preparing compounds of Formula Ifand IIf.

Process D relates, more preferably, to the halogenation1-alkyl-3-aryl-5-haloalkyl pyrazoles to form 4-halo pyrazoles. Thehalogenated pyrazoles of Formula If are prepared by halogenating acompound of Formula Ie according to the reaction ##STR55## wherein R¹ isC₁₋₅ alkyl, R² is C₁₋₃ haloalkyl, and R³, R⁵ and R⁶ are halogen.Suitable halogenating agents known in the art include chlorine,N-chlorosuccinimide, sulfuryl chloride, bromine, N-bromosuccinimide,etc. The amount of halogenating reagent can range from less than onemolar equivalent to an excess, relative to the 3-aryl pyrazole compoundsof Formula Ie. Any inert solvent may be used, including organic acids,inorganic acids, hydrocarbons, halogenated hydrocarbons, aromatichydrocarbons, ethers, sulfides, sulfoxides and is sulfones. Reactiontemperatures may range from about 10° C. to about 100° C. and thereaction period will vary depending on reagent concentrations,temperature, etc.

R³ is preferably a bromo group, and Process D relates, in a preferredembodiment, to the bromination of heterocyclic compounds such as a1-alkyl-3-aryl-5-haloalkyl pyrazole. A compound of Formula Ie may bebrominated to prepare a brominated pyrazole of Formula If (with R³ asbromo), by reacting the compound of Formula Ie with a bromonium ion. Thebromonium ion is preferably generated by oxidizing a bromide salt. Bothorganic and inorganic bromide salts are suitable, with inorganic bromidesalts such as alkali bromides (e.g. sodium bromide) being preferred.Preferred oxidizing agents include, independently, aqueous sodiumhypochlorite and chlorine gas. The bromonium ion may, alternatively, bepresent as bromonium chloride, BrCl, formed for example by mixing Br₂(g) and Cl₂ (g). Advantageously, bromonium ion generated from a bromidesalt under oxidizing conditions is generally more reactive and moreselective than liquid bromine. Reaction times using this system areshorter than those using liquid bromine by an order of magnitude.Moreover, the bromination reagents used herein are generally lessexpensive than liquid bromine, and the present method minimizes thequantity of bromide waste which is generated.

The reaction may be carried out in any suitable solvent, but ispreferably conducted using aliphatic acid solutions such as acetic acid.The use of an acetic acid solution helps minimize undesired sidereactions, such as halogenation of the benzoic acid to an acid halide.

Preferably, excess sodium bromide is added to an acetic acid solutioncontaining a compound of Formula Ie. The total amount of sodium bromidein the reaction mixture preferably ranges from about 1.0 to about 1.6molar equivalents relative to the amount of benzoic acid substrate ofFormula Ie, more preferably from about 1.15 to about 1.5 molarequivalents with about 1.4 equivalents being most preferred. Note thatwhen the reagent compound of Formula Ie is supplied directly from theprevious oxidation step, the existing mixture may already contain arelatively small amount of NaBr which was used as a promoter duringoxidation. In such a case, the amount of NaBr already existing insolution should be accounted for in determining the amount of NaBr toadd. The sodium bromide is preferably added as an aqueous solutionformed by dissolving the NaBr in distilled or deionized water (about 17to about 25 molar equivalents H₂ O, with about 21 molar equivalentsbeing preferred). The reaction mixture should be well mixed while addingNaBr and during the subsequent reaction to achieve good brominationyield and minimize side reactions. The sodium bromide is preferablyadded slowly to minimize the formation of large lump precipitates and tominimize significant temperature departures below about 70° C. Theoxidation agent is added and the reaction mixture is heated to thedesire reaction temperature, which preferably ranges from about ambienttemperature to about 100° C., more preferably from about 70° C. to about90° C., and most preferably from about 75° C. to about 85° C.

When chlorine gas is used as the oxidizing agent, excess chlorine isslowly added, while mixing, to the reaction mixture. The amount ofexcess chlorine preferably ranges from about 1.0 to about 1.5 molarequivalents relative to the amount of heterocyclic substrate of FormulaIe. When the oxidized aryl-pyrazole product resulting from Process C issubsequently brominated in the instant process without being isolated,the amount of excess chlorine preferably ranges from about 1.0 to about1.3 molar equivalents relative to the amount of substituted toluenesubstrate of Formula Id (Process C), with about 1.15 molar equivalentsbeing most preferred. Without being bound by theory, it is believed thatthe chlorine reacts with aqueous sodium bromide to form bromonium ion,Hcl and NaCl, and the bromonium ion brominates the substrate. Thereaction following the addition of chlorine gas is fairly exothermic. Asthe reaction progresses, the reaction mixture typically becomes moreviscous, and may require higher temperatures and/or the addition of morewater to facilitate proper mixing. If the reaction does not reachcompletion, as determined by HPLC or fluorine NMR, additional chlorine(about 0.1 molar equivalent) may be added.

When sodium hypochlorite is used as the oxidizing reagent, excess sodiumhypochlorite is added after the sodium bromide has been added and mixedwith the substrate compound. The NaOCl is preferably added as an aqueoussolution while the reaction mixture is stirred and maintained at about70° C. The amount of excess NaOCl preferably ranges from about 1.0 toabout 3.0 molar equivalents relative to the amount of heterocyclicsubstrate of Formula Ie. When the oxidized aryl-pyrazole productresulting from Process C is subsequently brominated in the instantprocess without being isolated, the amount of excess hypochloritepreferably ranges from about 1.5 to about 3.5 molar equivalents relativeto the amount of substituted toluene substrate of Formula Id (ProcessC), with about 2.5 molar equivalents being most preferred. The reactionthen proceeds as described above with respect to using chlorine as theoxidizing agent. The sodium hypochlorite and chlorine gas are equallypreferred as oxidizing agents based on performance. However, preferencebetween these oxidizing agents may be based on other factors, such asavailability. Other oxidizing agents known to those skilled in the artmay also be used. Regardless of the oxidizing agent employed, thebromination reaction is preferably carried out at atmospheric pressure.Reaction times may vary from a few minutes to several days, with yieldsof greater than about 90% resulting in about 2-4 hours at temperaturesranging from about 75° C. to about 85° C.

When the reaction is completed, the reaction mixture is cooled to aboutambient temperature or slightly greater. The excess oxidizing agent isthen destroyed and the desired brominated pyrazole product isprecipitated out of solution. Where the NaOCl/NaBr or Cl(g) systems areused, residual oxidizing agent may be destroyed and a precipitatedproduct formed by adding an aqueous solution of reducing agent such asaqueous sodium sulfite solution to the reaction mixture. Additionalwater may be added to fully precipitate the desired product and to aidmixing. After waiting a period of time for dissolution of inorganicsalts in the reaction mixture (about 15 to about 30 minutes), theprecipitated product may then be filtered from solution, washed withdeionized water and dried. Where the resulting halogenated pyrazolecompound of Formula If will be used in the subsequent esterificationstep, the product should be thoroughly dried.

In a most preferred embodiment, the brominated-aryl-pyrazole of FormulaIIf is prepared from the compound of Formula IIe according to thereaction: ##STR56## This reaction is carried out substantially asdescribed above for preparing compounds of Formula If, and is furtherexemplified in Example 1 (Processes D-1 and D-2).

Process E

Process E relates to the esterification of carboxylic acids. While thesubstrate for this reaction is preferably a 2,4-dihalo-5-pyrazolebenzoic acid, the esterification methods of the present invention aremore generally applicable to other carboxylic acids, including aliphaticcarboxylic acids, long-chain fatty acids, heterocyclic carboxylic acids,substituted and unsubstituted benzoic acids, and benzoic acidssubstituted with at least one substituent being a(n) (un)substitutedheterocyclic ring having up to 6 ring members. In particular, theesterification methods presented herein may be used to prepare a benzoicacid ester of Formula IIIi from a compound of Formula IIIg according tothe reaction ##STR57## wherein Pyr is pyrazole or substituted pyrazoleas defined for Process C, R⁵ and R⁶ are halogen, and R¹⁰ is C₁₋₅ alkyl.The esterification of such substrates is carried out via either of twoesterification protocols, as described in more detail below forpreparing compounds of Formulas I and II.

In a more preferred process, a 2,4-dihalo-5-pyrazole-benzoic acid esterof Formula I is prepared by esterifying a compound of Formula Ifaccording to either of two protocols which effect the reaction:##STR58## wherein R¹ is C₁₋₅ alkyl, R² is C₁₋₃ haloalkyl, R³, R⁵ and R⁶are halogen and R¹⁰ is C₁₋₅ alkyl. Briefly, in a first esterificationprotocol, a benzoic acid of Formula If is reacted with a halogenatingagent to form a corresponding acid halide. The acid halide is thenstirred with an excess of esterification reagent formed by premixing anesterifying alcohol with an acyl halide. In an alternative protocol forpreparing the benzoic acid ester of Formula I, the benzoic acid ofFormula If is esterified with a trialkylorthoester. Each of theseesterification protocols are particularly suited to esterifying with ahindered --OR group, such as isopropyl.

In the first esterification protocol, the acid halide intermediate isprepared by methods known in the art. An exemplary method includesreacting the benzoic acid substrate with a halogenating agent such asthionyl chloride, phosphorus pentachloride, oxalyl chloride, etc. Inertsolvents such as toluene, which do not interfere with the halogenationreaction, may be used, and the reaction may be promoted by adding acatalytic amount of an amine base such as triethylamine, pyridine ordimethylformamide, etc. Preferably, the benzoic acid substrate ishalogenated by mixing the substrate with excess halogenating agent(1.1-1.7 equivalents) in a toluene solution at ambient temperature,adding a few drops of dimethylformamide, slowly heating to about 75° C.and reacting at that temperature for about 1 to 3 hours. Other reactiontemperatures and periods may be appropriate. After forming the acidhalide intermediate, the toluene solvent and excess halogenating agentare removed by stripping in vacuo while maintaining the temperature atabout 75° C.

The acid halide intermediate is reacted with an esterification reagentformed by mixing a small amount of an acylhalide with an alcohol ofFormula R¹⁰ OH. The acyl halide is preferably a C₁₋₃ acyl halide, andmore preferably an acetyl halide. The halide member of the acyl halideshould generally be the same halide as the acid halide intermediatebeing esterified, and is preferably chloride. A most preferred acylhalide is acetyl chloride. The amount of acyl halide added to form theesterification agent preferably ranges from about 0.1% to about 10%,more preferably from about 2% to about 5%, and is most preferably about4%, by weight, relative to amount of alcohol added to form theesterification agent. While not being bound by theory, acyl halides suchas acetyl chloride are believed to scavenge any trace H₂ O which may bepresent in the alcohol reagent stock, thereby eliminating a potentiallycompeting reaction when the esterifying alcohol is subsequently reactedwith the acid halide intermediate being esterified. The acetyl halideappears to react preferentially with water rather than with the alcohol,particularly where the alcohol is a hindered alcohol such asisopropanol. As such, the use of a acylhalide/alcohol esterificationreagent allows for the use of less expensive alcohol grades (ie, gradeshaving from about 1% to about 2% water) while providing for improvedyields and purity of the resulting ester product. An exotherm and theevolution of Hcl gas may be expected when the acylhalide and alcohol aremixed to form the esterification agent. An excess of esterificationagent (about 5 to 15 molar equivalents and preferably about 10 molarequivalents) is added to the acid halide intermediate and the reactionproceeds at atmospheric pressure and at a temperature maintained torange from about 0° C. to about the boiling point of the alcohol. Whenisopropanol is used as the esterifying alcohol, the temperature ispreferably maintained to range from about 0° C. to about 80° C., with atemperature of about 75° C. being most preferred. Hcl gas results fromthe esterification reaction and should be scrubbed during the reaction.The reaction period varies, but yields greater than about 90% areobtained by reacting at about 75° C. for about one to two hours. Theresulting esterification product is also of high purity (greater thanabout 90%), which simplifies product workup and results in improvedpayloads and cycle times. The resulting benzoic acid ester product canbe isolated by removing excess alcohol in vacuo or by precipitating theproduct. In the former isolation method, the reaction mixture ispreferably heated to and maintained at a temperature of about 80° C. toabout 90° C. while the alcohol solvent and other volatiles are strippedunder reduced pressure. The remaining mixture containing the product isthen cooled to ambient temperature. Alternatively, the product may beprecipitated by cooling to about 50° C. and adding water, and thenisolated by filtering.

In the alternative esterification protocol, the benzoic acid ester ofFormula I is prepared by reacting the benzoic acid of Formula If with atrialkylorthoester of Formula F1, ##STR59## wherein in the aboveformula, R¹⁰ is C₁₋₅ alkyl and R¹¹ is hydrogen or alkyl. R¹⁰ ispreferably C₃₋₅ alkyl. R¹¹ is preferably hydrogen such that thetrialkylorthoester is a trialkylorthoformate. Advantageously,trialkylorthoesters such as trialkylorthoformates provide excellentyield of the desired alkyl esters.

The benzoic acid is esterified with the trialkylorthoester in neat or ina suitable solvent. Where solvent systems are used, aromatic hydrocarbonsolvents such as toluene, xylene and cymene and relatively high-boilingethers such as methoxyethylether, diethoxyether or dioxane are suitablesolvents. Preferably, the benzoic acid substrate is mixed with excesstrialklyorthoester (about 1.1 to about 1.5 molar equivalents with about1.3 molar equivalents being preferred) and heated to a reactiontemperature ranging from about 80° C. to about 150° C., more preferablyfrom about 130° C. to about 140° C., and most preferably at about 135°C. Volatile by-products begin to be driven out of the reaction mixtureas the reaction mixture is heated above about 110° C. The reaction ispreferably carried out at atmospheric pressure. The reaction time variesdepending on the temperature and the concentration of reactants; yieldsof about 90% are typically obtained using at a temperature of about 135°C. for about 1 to 2 hours. After the reaction, the esterified productmay be isolated as a melt by stripping away excess trialkylorthoformate,solvent and volatile by-products, and then cooling. Alternatively, theesterified product may be precipitated by cooling to about 50° C.,adding isopropanol and then adding water. The precipitated product isisolated by filtering, optionally rewashing with additionalisopropanol/water, and drying.

In a most preferred embodiment, the esterified aryl-pyrazole of FormulaII is prepared from the compound of Formula IIf according to thereaction: ##STR60## This reaction may be effected substantially asdescribed above using either of the two esterification protocols forpreparing compounds of Formula I. Where the first esterificationprotocol is used, a preferred esterification reagent for preparing theisopropyl ester is formed by mixing about 4% acetyl chloride, by weight,with isopropanol. Where the second esterification protocol is used, thetrialkylorthoester esterification reagent is preferablytriisopropylorthoformate, where, with reference to Formula F1, R¹⁰ isisopropanol (--CH(CH₃)₂) and R¹¹ is hydrogen. The formation of theisopropyl ester of Formula II is further exemplified in Example 1(Processes E-1 and E-2) for the acylhalide/alcohol andtrialkylorthoester protocols, respectively.

Order of Process Steps

The process steps for preparing compounds of Formulas I or II arepreferably carried out in the order of Processes A-E as presented above:diketone formation (Process A), cyclization (condensation) andalkylation (Process B), oxidation (Process C), halogenation (Process D)and esterification (Process E). However, the exact order is not narrowlycritical, and may be varied by persons skilled in the art.

For example, the order of the halogenation step may be varied.Halogenation can be carried out between the alkylation and oxidationsteps of the preferred order. With reference to the process stepsdescribed above, aryl-pyrazole compounds may be prepared by forming aphenyl diketone from an acetophenone (Process A), condensing thephenyl-diketone and alkylating to form an alkylated pyrazole (ProcessB), halogenating the pyrazole moiety (Process D), oxidizing the methylgroup on the phenyl moiety (Process C) and esterifying (Process E).Compounds of Formula I are prepared according to this embodiment byacylating a compound of Formula Ia (Process A) ##STR61## to form acompound of Formula Ib, ##STR62## condensing the compound of Formula Ibwith hydrazine to form an alkyl-pyrazole-precursor intermediate andalkylating the intermediate (Process B) to form a compound of FormulaId, ##STR63## halogenating the compound of Formula Id (Process D) toform a compound of Formula Ig ##STR64## oxidizing the compound ofFormula Ig (Process C) to form a compound of Formula If, and ##STR65##esterifying the compound of Formula If (Process E) to form a compound ofFormula I.

Additionally, the pyrazole moiety could be halogenated after theoxidation and esterification steps. In such a case, the aryl-pyrazolesare prepared by forming a phenyl diketone (Process A), condensing thephenyl-diketone and alkylating to form an alkylated pyrazole (ProcessB), oxidizing the methyl group on the phenyl moiety to form a benzoicacid pyrazole (Process C), esterifying the benzoic acid (Process E), andhalogenating the pyrazole moiety (Process D). Compounds of Formula I areprepared by acylating a compound of Formula Ia (Process A) ##STR66## toform a compound of Formula Ib, ##STR67## condensing the compound ofFormula Ib with hydrazine to form an alkyl-pyrazole-precursorintermediate and alkylating the intermediate (Process B) to form acompound of Formula Id, ##STR68## oxidizing the compound of Formula Id(Process C) to form a compound of Formula Ie, ##STR69## esterifying thecompound of Formula Ie (Process E) to form a compound of Formula Ih, and##STR70## halogenating the compound of Formula Ih (Process D) to form acompound of Formula I.

Another variation to the order of the process steps for preparingaryl-pyrazoles includes oxidizing and esterifying the phenyl moietybefore forming the pyrazole. For example, aryl-pyrazoles may be preparedby first oxidizing a methyl-acetophenone to form a carboxylicacid-acetophenone (Process C), esterifying (Process E), forming a phenyldiketone (Process A), condensing the phenyl-diketone and alkylating toform an alkylated pyrazole (Process B) and halogenating the pyrazolemoiety (Process D). In particular, compounds of Formula I may beprepared by oxidizing a compound of Formula Ia (Process C) ##STR71## toform a compound of Formula Ii, ##STR72## esterifying the compound ofFormula Ii (Process E) to form a compound of Formula Ij ##STR73##acylating the compound of Formula Ij (Process A) to form a compound ofFormula Ik ##STR74## condensing the compound of Formula Ik withhydrazine to form an alkyl-pyrazole-precursor intermediate andalkylating the intermediate (Process B) to form a compound of FormulaIh, and ##STR75## halogenating the compound of Formula Ih (Process D) toform a compound of Formula I.

As another example, an aryl-pyrazole may be prepared by first forming aphenyl-diketone (Process A), oxidizing (Process C) a methyl group on thephenyl moiety of the phenyl-diketone, esterifying (Process E), formingan alkylated pyrazole (Process B) and halogenating (Process D).According to this process, a compound of Formula I may be prepared byacylating a compound of Formula Ia (Process A) ##STR76## to form acompound of Formula Ib, ##STR77## oxidizing the compound of Formula Ib(Process C) to form a compound of Formula Il, ##STR78## esterifying thecompound of Formula Il (Process E) to form a compound of Formula Ik, and##STR79## condensing the compound of Formula Ik with hydrazine to forman alkyl-pyrazole-precursor intermediate and alkylating the intermediate(Process B) form a compound of Formula Ih, ##STR80## halogenating thecompound of Formula Ih (Process D) to form a compound of Formula I.

In still another variation in order, the oxidation step could be carriedout before pyrazole formation with the esterification being carried outafter pyrazole formation. For example, an aryl-pyrazole may be preparedby first oxidizing a methyl-acetophenone to form a carboxylicacid-acetophenone (Process C), then forming a phenyl diketone (ProcessA), and condensing the phenyl-diketone and alkylating to form analkylated pyrazole (Process B), halogenating the pyrazole moiety(Process D) and esterifying (Process E). Specifically, compounds ofFormula I may be prepared by oxidizing a compound of Formula Ia (ProcessC) ##STR81## to form a compound of Formula Ii, ##STR82## acylating thecompound of Formula Ii (Process A) to form a compound of Formula Il##STR83## condensing the compound of Formula Il with hydrazine to forman alkyl-pyrazole-precursor intermediate and alkylating the intermediate(Process B) to form a compound of Formula Ie, ##STR84## halogenating thecompound of Formula Ie (Process D) to form a compound of Formula If, and##STR85## esterifying the compound of Formula If (Process E) to form acompound of Formula I.

As another example, an aryl-pyrazole may be prepared by first forming aphenyl-diketone (Process A), oxidizing (Process C), forming an alkylatedpyrazole (Process B), halogenating (Process D), and esterifying (ProcessE). 3-aryl-pyrazoles of Formula I may be prepared by acylating acompound of Formula Ia (Process A) ##STR86## to form a compound ofFormula Ib, ##STR87## oxidizing the compound of Formula Ib (Process C)to form a compound of Formula Il, ##STR88## condensing the compound ofFormula Il with hydrazine to form an alkyl-pyrazole-precursorintermediate and alkylating the intermediate (Process B) to form acompound of Formula Ie, ##STR89## halogenating the compound of FormulaIe (Process D) to form a compound of Formula If, and ##STR90##esterifying the compound of Formula If (Process E) to form a compound ofFormula I.

Additionally, the halogenation step could, in these last two examples,be carried out after the esterification. Using this variation, compoundsof Formula I may be prepared by acylating a compound of Formula Ia(Process A) ##STR91## to form a compound of Formula Ib, ##STR92##oxidizing the compound of Formula Ib (Process C) to form a compound ofFormula Il, ##STR93## condensing the compound of Formula Il withhydrazine to form an alkyl-pyrazole-precursor intermediate andalkylating the intermediate (Process B) to form a compound of FormulaIe, ##STR94## esterifying the compound of Formula le (Process E) to forma compound of Formula Ih, and ##STR95## halogenating the compound ofFormula Ih (Process D) to form a compound of Formula I.

As another exemplary variation in the preferred order of process steps,aryl-pyrazoles of Formula I may be prepared by oxidizing a compound ofFormula Ia (Process C) ##STR96## to form a compound of Formula Ii,##STR97## acylating the compound of Formula Ii (Process A) to form acompound of Formula Il ##STR98## condensing the compound of Formula Ilwith hydrazine to form an alkyl-pyrazole-precursor intermediate andalkylating the intermediate (Process B) to form a compound of FormulaIe, ##STR99## esterifying the compound of Formula Ie (Process E) to forma compound of Formula Ih, and ##STR100## halogenating the compound ofFormula Ih (Process D) to form a compound of Formula I. In each of theaforementioned alternative reaction sequences, R¹ is C₁₋₅ alkyl, R² isC₁₋₃ haloalkyl, R³, R⁵ and R⁶ are halogen and R¹⁰ is C₁₋₅ alkyl.

Those skilled in the art will appreciate that yet additional variationsin order may be used to prepare aryl-pyrazoles according to theprocesses of the present invention. The following examples illustratethe principles and advantages of the invention.

EXAMPLES Example 1

Preparation of isopropyl 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate

Process A

1,1,1-trifluoro-4-4-chloro-2-fluoro-5-methyl-phenyl-1-yl!-2,4-dibutanone (Formula IIb) wasprepared from a compound of Formula IIa according to the reaction:##STR101## Trifluoroacetyl chloride (2.6 kg, 1.5 molar equiv. relativeto the compound of Formula IIa) was bubbled into a solution containing25% sodium methoxide in methanol (4.24 kg NaMeO, 1.5 molar equiv.relative to the compound of Formula IIa) at -5° C. The addition wascontrolled so that the temperature did not exceed 40° C., despite theresulting exotherm. Total addition time was about 1.5 hours. The4-chloro-2-fluoro-5-methyl-acetophenone of Formula IIa (2.434 kg, 13.092mole) was then added. An additional amount of the sodiummethoxide/methanol solution (4.24 kg, 1.5 molar eq.) was added, a mildexotherm was noted, and the reaction mixture was heated to 60° C. andmaintained at that temperature for the course of the reaction. Theprogress of the reaction was monitored by gas chromatography, whichindicated completion in about 45 minutes.

In preparation for the cyclization reaction of Process B. the resultingcompound of Formula IIb was worked up as follows. A 10% aqueous HClsolution (5.0 kg) was added to neutralize the reaction. The methanol wasthen stripped at 45°-50° C. with a slight vacuum to result in a slurry.Toluene (11.62 kg) was added as a solvent and the aqueous layer wasremoved. The toluene solution, which contained the product compound ofFormula IIb, was washed with DI water (6.63 kg) and used directly inProcess B without further processing.

Alternative methods for working up the product compound of Formula IIbwere used in additional experiments. In one alternative method, forexample, methanol was first stripped at 45°-50° C. with a slight vacuumand resulted in a slurry. The temperature was cooled back to ambienttemperature and toluene (11.62 kg) was added as solvent. The toluenesolution was washed first with a 10% aqueous HCl solution (5.0 kg) andthen with DI water (6.63 kg). The aqueous layer was removed and thetoluene solution was used in Process B without further processing. Inanother work-up method, the reaction was first cooled to 50° C., andthen neutralized with a 10% aqueous HCl solution (7.0 kg). The solutionwas further cooled to about 10° C., resulting in a precipitated product.The precipitate was isolated by filtration and then washed with DI wateruntil filtrate pH was greater than about 2. To use the isolated compoundin Process B, the isolated precipitate was reslurried in toluene (about11 kg) without further drying.

Process B

1-methyl-3-4-chloro-2-fluoro-5-methyl-phenyl-1-yl!-5-trifluoromethyl-pyrazole(Formula IId) was from the compound of Formula IIb according to thereaction: ##STR102## 35% aqueous hydrazine (1.1 molar equivalents) wasadded at ambient temperature to a toluene solution containing1,1,1-trifluoro-4-4-chloro-2-fluoro-5-methyl-phenyl-1-yl!-2,4-dibutanone (Formula IIb),prepared as described above. A mild exotherm was noted and thetemperature was maintained at about 40° C. throughout the condensationreaction. The reaction mixture was stirred at 40° C. for 30 minutes andreaction progress was monitored by gas chromatography. In someexperimental runs, some of the intermediate products precipitated out ofsolution during the course of the reaction.

Upon completion of the reaction, the reaction mixture was, whennecessitated, heated to 70° C. to redissolve precipitated intermediatesand/or to facilitate separation of the organic and aqueous phases intodistinct layers. The water layer was removed and the toluene solutionwas washed with a 10% aqueous brine solution (2×2.77 kg). The aqueousbrine solution was then removed and discarded.

Dimethylsulfate (1.94 kg, about 1.2 equiv.) was added slowly to thetoluene solution containing the alkyl-pyrazole-precursor intermediates,prepared as described above, the speed of addition being controlled soas to minimize large exotherms. After addition of dimethylsulfate, thesolution was heated to reflux at 105° C. while azeotroping to removewater. The reaction progress was monitored by gas chromatography. Inexperimental runs where the reaction did not go to completion,additional dimethyl sulfate (about 150 to 170 grams) was added. Afterrefluxing for about 10 hours, the solution was cooled, washed with anaqueous 10% NaOH solution (5.16 kg), washed with an aqueous 5% NaOHsolution (5.16 kg), and then washed with an aqueous 10% brine solution(5.16 kg). Toluene was stripped from the solution and replaced withmethanol (2.95 kg). The alkylated pyrazole reaction product wasprecipitated by adding water (184 grams, 1:16 weight ratio relative tomethanol) and then cooling to about 5° C. The precipitated product(about 2.858 kg, light grey solid) was removed by centrifuging. Theoverall yield for the combined steps of Processes A and B was about 75%.

Process C

5- 1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid (Formula IIe) was prepared from the compound of Formula IIdaccording to the reaction: ##STR103## 1-methyl-3-4-chloro-2-fluoro-5-methyl-phenyl-1-yl!-5-trifluoromethyl-pyrazole ofFormula IId (2.853 kg, 9.755 moles), prepared as described above,Co(OAc)₂ 4H₂ O (24.16 g, 0.098 mole), Mn(OAc)₂ H₂ O (2.4 g, 0.0097moles) and NaBr (30.24 g, 0.277 moles) were added to a reactor. Glacialacetic acid (11.00 kg, 184 moles) was then added, followed in successionby the addition of benzoyl peroxide (22.87 g, 0.094 moles--supplied as32.67 g of a hydrated solid comprising 70% benzoyl peroxide) and acetone(27.66 g, 0.49 moles). Mixing of the substrate, catalysts, promoters andinitiator as a reaction mixture was then initiated and continuedthroughout the reaction. Air at atmospheric pressure was introduced intothe reaction mixture. The reaction mixture was heated to about 110° C.and maintained at that temperature throughout the reaction. Reactionprogress was monitored using HPLC, and the reaction was typicallycomplete within about 10-20 hours. The reaction mixture containing theproduct was not isolated or otherwise worked-up, in anticipation ofbeing used in the bromination reaction, described below.

Variations in the aforementioned oxidation experiments were carried out.In experimental runs in which the reaction had been carried out asdescribed above except for the use of hydrogen peroxide instead ofbenzoyl peroxide, initiation of the oxidation reaction was erratic andsometimes took as long as six hours. In experimental runs in which thereaction had been carried out as described above except that acetone hadnot been added to the reaction mixture, the time necessary for thereaction to proceed to completion was about 20% to about 30% longer. Infurther experimental runs using the preferred reaction mixture, oxygenwas used in place of air, and independently, elevated pressures wereused with both air and oxygen as the purge gas. Moreover, in someexperimental runs, the reaction product was isolated by cooling andadding water. The reaction typically resulted in better than about 90%yield of oxidized benzoic acid product at a purity of about 93% to about97%.

Process D-1

5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid (Formula IIf) was prepared from the compound of Formula IIeaccording to the reaction: ##STR104## A slurry containing 5-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid in about four parts acetic acid was prepared as described inProcess C. Sodium bromide (1.36 kg, 1.35 molar equiv.) was dissolved indeionized water (3.69 kg, about 21 molar equiv.) and slowly added to theacetic acid substrate solution. The addition of NaBr was carried outwith aggressive mixing and with care to maintain the temperature aboveabout 70° C. to minimize precipitation in large lumps. Cl₂ gas (789 g,1.15 molar equiv.) was added, resulting in an exotherm. The reactionmass became thicker as the reaction progressed, and the temperature wasmaintained at about 85° C. to facilitate agitation. Reaction progresswas monitored independently by HPLC. and fluorine NMR. In cases wherethe reaction did not proceed to completion, additional chlorine (74 g,0.1 molar equiv.) was added. The reaction was complete within about 3hours after the end of chlorine addition.

The reaction mixture was then cooled to ambient temperature and quenchedwith a 25% aqueous sodium sulfite solution (about 2.8 kg, 0.15 molarequiv.). Additional water (3.69 kg, 20 molar equivalents) was added toaid mixing and to fully precipitate the brominated product. Afterwaiting about 30 minutes, the product was isolated by filtration, washedwith DI water, and thoroughly dried in preparation for subsequent use inProcess E. Approximately 3.50 kg of brominated aryl-pyrazole product(Formula IIf) was isolated having a purity of between about 93-97% andresulting in a yield of about 80% to about 90% relative to the alkylatedpyrazole compound of Formula IId.

Process D-2

The bromination was performed as described above (Process D-1) exceptsodium hypochlorite was used instead of chlorine gas as the oxidingagent. After sodium bromide (1.36 kg, 1.35 molar equiv.) was dissolvedin deionized water (3.69 kg, about 21 molar equiv.) and added to theslurry containing 5-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid in acetic acid, an aqueous NaOCl solution (1.5-2.4 molar equiv.)was added slowly while stirring and while maintaining the temperature at70° C. Reaction progress was monitored by HPLC and the reaction wascomplete within about 3 hours after the addition of NaOCl. Aftercompletion of reaction, the solution was cooled and quenched with sodiumsulfite as described above. The product was isolated as described abovewith similar yields.

Process E-1

Isopropyl 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoate(Formula II) was prepared from the compound of Formula IIf according tothe reaction ##STR105## 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid(3.50 kg) prepared as described above and thoroughly dried wasdissolved in toluene (7.38 kg, 9 molar equiv.) at ambient temperature.Thionyl chloride (1.58 kg, 1.5 molar equiv.) and dimethyl formamide (9.2g, 0.01 molar equiv.) were added thereto at 25° C., and the reactionmixture was slowly heated to 75° C. The heating rate was controlled soas to minimize foaming of the solution. The reaction progressed at 75°C. and was complete within about 2 hours. The toluene solvent and excessthionyl chloride were stripped in vacuo while maintaining thetemperature at 75° C., leaving the corresponding acid chlorideintermediate (about 3.8 kg) as an oil.

Reagent grade isopropanol (5.53 kg, 10.6 molar equiv.) was mixed withacetyl chloride (221 g) to form an esterification agent. An exotherm andevolution of HCl gas was observed. The esterification agent was added tothe acid chloride intermediate at 75° C. The reaction mixture wasstirred and maintained at a temperature of 75° C. during the reaction,and HCl off gas was scrubbed. Reaction progress was monitored by gaschromatography and was complete within about 2 hours.

The reaction mixture was then cooled to about 50° C. Water (11 kg) wasslowly addend to precipitate the product. The product was isolated byfiltration, resulting in a tan to white waxy solid with a purity ofgreater than about 92% and a yield of about 90% to about 94%.

In other experiments, an alternative method for product work-up includedstripping the product mixture under reduced pressure and at temperaturesranging from about 80° to about 90° C. to remove solvent and allvolatiles. The melt was then cooled to ambient temperatures to form abrick-like solid.

Process E-2

In an alternative esterification protocol, 5-4-bromo-1-methyl-5-(trifluoromethyl)-1H-pyrazole-3-yl!-2-chloro-4-fluorobenzoicacid (300 g, 0.747 moles), prepared as described above, was mixed withtriisopropylorthoformate (186 g, 1.3 molar equiv.) and then heated toabout 135° C. to about 140° C. with removal of the low-boilingby-product. The reaction was monitored by HPLC and was completed withinabout 1.5 hours.

Excess triisopropylorthoformate and volatile by-products were strippedat reduced pressure, and the resulting oil was cooled and isolated as amelt. In other experiments, the product was precipitated by cooling thereaction mixture to about 50° C., adding isopropanol (480 g), andsubsequently adding water (600 g). The precipitated product was furtherwashed with a water/isopropanol solution (240 g, 1:0.8 ratio ofwater:isopropanol, by weight). The product was isolated by filtration,and dried. Product purity was greater than about 92 percent and yieldwas about 90%.

Example 2

Preparation of 3(5)-4-chloro-2-fluoro-5-methylphenyl-1-yl!-5(3)-(trifluoromethyl)-1H-pyrazole.

3(5)-4-chloro-2-fluoro-5-methylphenyl-1-yl!-5(3)-(trifluoromethyl)-pyrazole,structurally represented as the compound of Formula IIc, ##STR106## wasprepared from 1,1,1-trifluoro-4-2-chloro-4-fluoro-5-methylphenyl-l-yl!-2,4-dibutanone. The dibutanone(20.6 g) was dissolved in 100 ml of acetic acid in a 500 ml flaskequipped with a magnetic stirrer. Hydrazine (2.85 g) was added all atonce and an exotherm to 45° C. was observed. The solution was heated to110° C. and maintained at that temperature for 15 minutes. The reactionmixture was then cooled to room temperature and poured into water (200ml), resulting in a white solid precipitate. The precipitated productwas isolated by filtering, and then air dried overnight. The solid waswashed with 200 ml of hexanes and air dried briefly to afford thearyl-pyrazole compound of Formula IIc (19.6 g) as a white solid (m.p.159°-160° C.; Anal. Calcd. for C₁₁ H₇ N₂ F₄ Cl₁ : C-47.42, H-2.53,N-10.05; Found: C-47.36, H-2.58, N-10.07). Product yield was about 97%

Example 3

Regioselective N-alkylation of 3(5)-aryl-5(3)-haloalkyl-pyrazoles

The preparation of regiospecific alkylated-pyrazoles of Formula IIIe,##STR107## were prepared from phenyl-diketones of Formula IIIb accordingto the reaction ##STR108## wherein in the above formulae, Ar is2,5-difluorophenyl and R² is CF₃. The compounds of Formula IIIb werecyclized with hydrazine, and the resulting intermediate(s) alkylatedwith a variety of methylating agents, CH₃ X, under different solvent andreaction conditions. The ratio percent of the resulting 3-aryl and5-aryl isomers for each of the several runs is shown in Table 3-1.

                  TABLE 3-1    ______________________________________             Conditions    Alkylating             (solvent,       % N-methyl products    agent    temperature)    3-Aryl   5-Aryl    ______________________________________    CH.sub.3 I             acetone, K.sub.2 CO.sub.3, RT                             70       30    CH.sub.3 I             DMF, K.sub.2 CO.sub.3, RT                             70       30    CH.sub.3 I             DMSO, K.sub.2 CO.sub.3, RT                             65       35    (CH.sub.3).sub.2 SO.sub.4             50% NaOH/CH.sub.2 Cl.sub.2, RT                             64       36    CH.sub.3 BR             acetone, K.sub.2 CO.sub.3, RT                             78       24    (CH.sub.3).sub.2 SO.sub.4             acetone, K.sub.2 CO.sub.3, RT                             77       23    CH.sub.3 BR             acetone, K.sub.2 CO.sub.3, 0° C.                             80       20    (CH.sub.3).sub.2 SO.sub.4             toluene, reflux 96       4    (CH.sub.3).sub.2 SO.sub.4             toluene, K.sub.2 CO.sub.3, RT                             55       45    ______________________________________

When the reaction was carried out under basic conditions using potassiumcarbonate or sodium hydroxide as a base, the percent of 3-aryl isomerselectively formed over the 5-aryl isomer ranged from about 55% to about80% of the total N-methyl pyrazoles products prepared, with the betterselectivity being obtained using less reactive methylating agents, suchas methyl bromide, and lower temperatures. However, significantlyimproved selectivity resulted by running the reaction under acidicconditions. Using a dimethylsulfate methylating agent in refluxingtoluene (forming methyl-sulfonic acid as the reaction proceeds), about96% of the alkylated aryl-pyrazole product was the desired 3-arylisomer. High-selectivity of the 3-aryl isomer was similarly obtainedwhen the reaction was repeated under acidic conditions, and when thesame reaction conditions (dimethylsulfate in refluxing anhydroustoluene) were used with different substituents on the phenyl group, asshown in Table 3-2.

                  TABLE 3-2    ______________________________________                       % N-methyl                       products    Ar                   3-Aryl  5-Aryl    ______________________________________    2,5-difluoro-phenyl  96      4    2,4-difluoro-phenyl  96      4    2,4-dichloro-phenyl  88      12    4-chloro-2-fluoro-5-methyl-phenyl                         91      9    ______________________________________

In each of the aforementioned reactions, the regiochemical assignment ofthe alkylated haloalkyl pyrazoles was determined by comparison of the ¹³C nmr chemical shifts of the 3 and 5 carbons of the pyrazole rings.Briefly, for the aryl substituent, the C3 carbon of the 3-aryl isomerhas greater hydrazone character and appears at about 143 ppm, whereasthe C5 carbon of the 5-aryl isomer has greater enehydrazine characterand appears upfield at about 133 ppm. These assignments are consistentwith the results of long-range coupling experiments and with an X-raystructure obtained for one 3-aryl isomer.

Example 4

Preparation of 3(5)-aryl-5(3)-difluorochloromethyl-pyrazole;decomposition of the same while alkylating under basic conditions andsuccessful alkylation of the same under acidic conditions

A 3-aryl-5-haloalkyl-pyrazole of Formula IIIc, ##STR109## wherein Ar was4-chlorophenyl and R² was CF₂ Cl was prepared from1,1-difluoro-1-chloro-4- 4-chlorophenyl-1-yl!-2,4-dibutanone. A solutionof the dibutanone (60.0 g, 0.240 moles) in glacial acetic acid (250 ml)was stirred and treated at once with hydrazine (0.253 moles, 8 ml). Asmall temperature increase was observed. The mixture was refluxed forone hour, allowed to cool, and added to water (500 ml). The product wasextracted with ether, combined extracts were washed with water followedby a 10% sodium bicarbonate solution and concentrated in vacuo to yieldthe aryl-pyrazole compound of Formula IIIc.

The aryl-pyrazole of Formula IIIc was alkylated under basic conditions(K₂ CO₃, MeI). However, the basic alkylation resulted in decompositionwithout any alkylated pyrazole products being formed. Theincompatibility of the CF₂ Cl group with base was confirmed by treatmentof the intermediate (Formula IIIc) with carbonate in the absence of analkylating agent. In this case, decomposition occurred in less than onehour at room temperature.

However, alkylation of an analogous 3-aryl-5-haloalkyl-pyrazole (with Aras 4-chloro-2-fluoro-5-methoxy-phenyl and R² as CF₂ Cl) was successfulunder acidic conditions. 5-4-chloro-2-fluoro-5-methoxy-phenyl-1-yl!-3-(chlorodifluoromethyl)-pyrazole(14.50 g, 0.0466 moles) in toluene was refluxed in a dean-stark trap forone hour, but no water was collected. Dimethyl sulfate (5.61 g, 0.0445moles) was added via syringe and the reaction mixture was refluxed for3.5 hours. The product mixture was washed with equal volume of NaOH(2.5N), and the organic layer was filtered. The solvent was removed invacuo and the resulting product was recrystallized four times insuccession from hexanes to result in an alkylated aryl-pyrazole (9.22 g,73% yield) of white crystalline solid (m.p. 73°-74° C.; Anal. Calcd. forC₁₂ H₉ N₂ OF₃ Cl₂ : C-44.33, H-2.79, N-8.62; Found: C-44.32, H-2.77,N-8.60)

In light of the detailed description of the invention and the examplespresented above, it can be appreciated that the several objects of theinvention are achieved.

The explanations and illustrations presented herein are intended toacquaint others skilled in the art with the invention, its principles,and its practical application. Those skilled in the art may adapt andapply the invention in its numerous forms, as may be best suited to therequirements of a particular use. Accordingly, the specific embodimentsof the present invention as set forth are not intended as beingexhaustive or limiting of the invention.

What is claimed is:
 1. A process for selectively oxidizing the alkylsubstituent of a benzene substrate wherein said benzene substrate has inaddition to its alkyl substituent a substituent which is a substitutedheterocyclic ring having up to six ring members, wherein theheterocyclic ring has at least one substituent chosen from the groupconsisting of C₁₋₅ alkyl groups and C₁₋₃ haloalkyl groups, the processcomprising reacting the benzene substrate with molecular oxygen in thepresence of a catalyst comprising a cobalt salt and a manganese salt, afirst catalyst promoter which is a bromide compound, and benzoylperoxide.
 2. The process as set forth in claim 1 wherein the alkyl groupof the benzene substrate is methyl.
 3. The process as set forth in claim1 wherein the substrate of Formula IIIf ##STR110## is oxidized to form acompound of Formula IIIg ##STR111## wherein: Pyr is a pyrazole orsubstituted pyrazole; and R⁵ and R⁶ are halogen.
 4. The process as setforth in claim 3 wherein Pyr is a substituted or unsubstitutedN-methyl-pyrazole.
 5. The process as set forth in claim 3 wherein Pyr isof Formula Pyr-1 ##STR112## wherein: R¹ is hydrogen, alkyl or alkylsubstituted with halogen, amino, nitro, cyano, hydroxy, carboxy, alkoxy,thio, mercaptoalkyl or alkylthio; and R² is alkyl, hydroxy, alkoxy,acyl, carboxylic acid and aldehyde, amide and ester derivatives thereof,halogen, haloalkyl, amino, nitro, cyano, mercaptoalkyl, alkylthio,alkylsulfinyl, alkylsulfonyl, alkylphosphinyl or alkylphosphonyl and R³is hydrogen or halogen.
 6. The process as set forth in claim 5 whereinR₁ is C₁₋₅ alkyl and R² is C₁₋₃ haloalkyl.
 7. The process as set forthin claim 5 wherein R¹ is methyl, R² is trifluoromethyl, R³ is hydrogenor bromo, R⁵ is fluoro and R⁶ is chloro.
 8. The process as set forth inclaim 1 which further comprises a second catalyst promoter which is aketone.
 9. The process as set forth in claim 8 wherein the secondcatalyst promoter is acetone.
 10. The process as set forth in claim 1wherein the substrate of Formula IId ##STR113## is oxidized in thepresence of a second catalyst promoter which is a ketone to form acompound of Formula IIe ##STR114##
 11. The process as set forth in claim1 wherein the substrate of Formula Ig ##STR115## is oxidized to form acompound of Formula If, ##STR116## wherein R¹ is C₁₋₅ alkyl, R² is C₁₋₃haloalkyl, and R³, R⁵ and R⁶ are halogen.
 12. The process as set forthin claim 1 wherein the substrate of Formula Ia ##STR117## is oxidized toform a compound of Formula Ii, ##STR118## wherein R⁵ and R⁶ are halogen.13. The process as set forth in claim 1 wherein the substrate of FormulaIb, ##STR119## is oxidized to form a compound of Formula Il, ##STR120##wherein R² is C₁₋₃ haloalkyl, R⁵ and R⁶ are halogen.